As the environmental interface, skin is subject to damage from many agents including ultraviolet (UV) irradiation, reactive oxygen species (ROS), and chemical carcinogens. DNA is perhaps the most critical target of such damage, and DNA mutations are chiefly responsible for the more than one million skin cancers annually in the U.S. Nucleotide excision repair and other constitutive mechanisms for detecting and repairing DNA damage have been extensively studied, but recent work demonstrates that mammalian cells also have an inducible capacity triggered by an initial DNA insult that evolves over several days and protects against subsequent damage. This inducible repair capacity, best demonstrated in skin, appears to be part of a multifaceted response also involving adaptive differentiation and apoptosis or proliferative senescence of cells at high risk for malignant conversion. We have shown that DNA oligonucleotides homologous to the telomere 3' overhang (T-oligos) induce the same protective responses in the absence of initial DNA damage, via p53 and p16/pRb signaling pathways. We hypothesize that exposure of the telomere 3' I-I'AGGG tandem repeat sequence, known to occur as a result of telomere disruption, also occurs after acute DNA damage or during aging and initiates signaling for protective anti-cancer responses. We further hypothesize that T-oligos mimic this physiologic signal. We propose to delineate the signaling pathways and biologic consequences of these protective responses in human keratinocytes, fibroblasts, and melanocytes, seeking subtle differences among them in activation of the p53 versus p16/pRb pathways that might explain the different susceptibilities and patterns of malignant conversion for these cell types. Using validated mouse models of the three major malignancies in human skin (basal cell carcinoma, squamous cell carcinoma, and melanoma), we will also test the hypothesis that pretreatment with T-oligos reduces the risk of malignancy after UV irradiation or chemical carcinogen exposure. Results from the proposed in vitro and in vivo studies should greatly enhance our understanding of telomere-based protective responses induced in mammalian cells and skin by acute DNA damage or multiple rounds of cell division. The studies will also explore the possible therapeutic potential of T-oligos that comparably induce these responses in the absence of actual DNA damage or telomere disruption.